Metastasis is the major cause of death in breast cancer patients,but the molecularnature of metustatic breast cancer is poorly understood. This limitedunderstandingis likely due to the genetic complexityof the metastatic phenotype, which is not easily studied using traditional methods. Little is known at thegenome- wide level about the degree of heterogeneity that may exist within primary tumors or the relationshipof this heterogeneity to eventual metastasis. Few studies have compared paired metastatic lesions and primary tumors; furthermore,most of these studies have been limited to the analysis of single or few molecular markers. Thus, the debate over whether a stochastic versus deterministic model of cancer metastasis is most relevant in breast cancer remains largely unresolved. A comprehensive understanding of the mechanisms of metastasis would greatly accelerate progress in the developmentof new diagnosticand therapeutic approaches to advanced breast cancer. Our long-term goal is to develop a more accurate understanding of the genetic alterations associated with progression of human breast cancer, througha systematic, genome-wide analysis of primary and metastatic lesions in patients with breast cancer. In addition, we will assess whether patterns of genetic alterationencoded in the primarytumor predispose to site-specific metastasis. To achieve these goals, we propose the following Aims: Specific Aim 1. To determine the degree and nature of genetic relatedness betweenpaired primary and metastatic lesions in human breast cancer patients using SNP microarrays. Specific Aim 2. To develop predictive models for site of eventual metastasisusing DNA microarray-based gene expression profiling of primary breasttumors.